Meeting Report. Central and peripheral mechanisms of aging and frailty: A report on the 8th longevity consortium symposium, Santa Fe, New Mexico, May 16-18, 2007

Arnold J. Kahn, Steven Austad, Marco Pahor, Tamara Harris, Bret Goodpaster, Christiaan Leewenburgh, Catherine Wolkow, Naftali Raz, Eric Klann, Roman Kondratov, Katie Stone, Adam Antebi, Marta Gaglia, John Tower, Rong Yuan

Research output: Contribution to journalArticlepeer-review


Although many biological gerontologists continue to study the effects of the insulin/IGF-I pathway on aging and longevity, as noted by Steve Austad, a pressing issue remains to demonstrate the applicability of the findings to humans. For example, individuals carrying a Laron or Laron-like growth hormone receptor mutation do not show the extended longevity and health characteristics of dwarf mice carrying similar gene defects. Frailty is a major and apparently ubiquitous feature of old age, observed in elderly humans, as well as in vertebrate and invertebrate animals, (e.g., see Wolkow above on aging C. elegans). Its defining features include slow movement, a reduction in muscle strength, and the loss of muscle mass or sarcopenia (Pahor, Harris, Goodpasture, and Leewenburgh). Although these age-related changes can be accounted for by a number of different mechanisms, two received particular attention at this meeting - accumulation of fat and lipids in muscle that occurs along with losses in mass and strength (Pahor, Goodpasture) and increased apoptosis in skeletal myofibers (Leewenburgh). In addition, iron accumulation is associated with the loss of muscle mass and strength and increased oxidative stress (Leewenburgh). Age-related changes in the normal human brain have received less attention than those associated with pathology (e.g., Alzheimer's disease, Parkinson's disease), so comprehensive documentation of what happens to the brain in the absence of disease is very welcome. As noted by Raz, losses in the quantity and quality of brain tissue with age show substantial variation in timing, rate of occurrence, and region of the brain affected. Significant individual differences in brain shrinkage patterns are also noted, with some of the variance attributable to identifiable genetic factors. Linking structural alterations in the aging brain to changes in function are even more challenging. Some insight into identifying the mechanisms that underlie brain aging was provided by Klann, who showed that transgene-mediated, overexpression of extracellular SOD was effective in mitigating age-related losses in hippocampus-dependent learning and memory. Whereas such changes were not realized in normal animals transgenic for mitochondrial SOD, expression of the latter in a mouse model of Alzheimer's disease did decrease amyloid deposition and improve spatial memory. Both findings underscore the importance of oxidative damage in brain aging and the potential for antioxidant-based interventions to help reverse or delay senescent changes in brain structure and function. The brain, of course, is not only a target of aging but also a likely contributor to age-related changes in other tissues and organs. Thus, the brain's suprachiasmatic nucleus helps establish and maintain circadian rhythms in mammals and, as illustrated in the presentations of Stone, Kondratov, and Tower, changes in these rhythms may be central to the aging process in humans and model organisms. Thus, Stone showed that disruption in the normal amplitude and timing of sleep-activity (circadian) rhythms in elderly women is associated with increases in all-cause mortality, cognitive dysfunction, and frailty. One mechanism by which this might occur was suggested by the findings of Kondratov - that genetic inactivation of a transcription factor (BMAL-1) involved in regulating circadian rhythms in mice results in accelerated, progeria-like aging, with animals dying at 9 months. Elevated levels of ROS can be detected in many organs in knockout mice and this finding, coupled with the presence of putative BMAL-1 binding sites in the promoter region of several antioxidant genes, suggests that the circadian system may coordinate antioxidant defenses through the BMAL-1 transcription factor. Tower and associates found that flies overexpressing mitochondrial SOD live longer, sustain stronger circadian rhythms, and show increased expression of Phase-II detoxification genes. These detoxification genes, like the target genes identified by Kondratov, share DNA-sequence motifs and therefore would be candidates for coordinate regulation by transcription factors involved in circadian rhythms and life-span determination. Caloric restriction is the best established environmental intervention for slowing the aging process and extending longevity. Although it is almost certain that it is the dietary change that is responsible for the latter effects, data from several laboratories, including the Kenyon Laboratory, indicate that olfactory input, originating from odorants in food, may play a role. For example, Gaglia (Kenyon Laboratory) showed that mutations affecting chemosensory function/olfaction in C. elegans also extend life span. Moreover, ablation of select neurons downstream of chemosensory input similarly increase longevity. Neurons, of course, are only one modality by which biological processes are controlled centrally. "Downstream" there are other mediators through which the aging of cells and tissues is modulated. Perhaps the most important of these are the hormones, some of which are, in fact, produced by neurons or neuroendocrine cells. As shown by Antebi, dafachronic acids, operating through the DAF-12 nuclear receptor play important roles in mediating dauer formation and aging in C. elegans. Dafachronic acids are bile acid-like steroids that have been shown to act as hormones in mammals. Interestingly, the dafachronic acid/DAF-12 pathway, like the downstream elements of the insulin/IGF-I pathway, helps regulate the DAF-16/FOXO transcription factor. Thus, the network of interactions involving insulin/IGF-I and longevity is still further enlarged.

Original languageEnglish (US)
Pages (from-to)1357-1360
Number of pages4
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Issue number12
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology


Dive into the research topics of 'Meeting Report. Central and peripheral mechanisms of aging and frailty: A report on the 8th longevity consortium symposium, Santa Fe, New Mexico, May 16-18, 2007'. Together they form a unique fingerprint.

Cite this